Inflammation is a ubiquitous clinical problem, yet its many forms are often intractable to currently available therapies.'A distinctive characteristic of many inflammatory diseases is their greater incidence and severity in women versus men. This proposal outlines an innovative strategy to create a foundation for the development of new approaches in the treatment of inflammatory disease: to determine the mechanisms by which sex and gonadal hormones modulate inflammation in order to suggest potential future therapies that target those endogenous modulatory pathways. We hypothesize that gonadal sex hormones differentially affect components of the inflammatory response in males and females through their regulation of neuroendocrine-immune circuits that strongly influence the inflammatory response. Our previous work has helped establish that the sympathoadrenal axis and its modulation by vagal afferents, both of which are sexually dimorphic, can powerfully impact the inflammatory response, and may thus also be important in establishing sexual dimorphism in inflammatory diseases. Our goal in this proposal is to elucidate the roles of gonadal hormones, the sympathoadrenal axis, and control of the sympathoadrenal axis by stress and by vagal afferent activity in the sexually dimorphic modulation of three principal components of the inflammatory response: plasma extravasation, leukocyte neutrophil function, and hyperalgesia. This study will employ an interdisciplinary approach using behavioral, cellular and molecular biological techniques to elucidate the mechanisms by which the nervous and immune system interact to produce sexual dimorphism of the inflammatory response. These data will have important implications for understanding and treatment of chronic inflammatory diseases in men and women.